Up-regulation of tumor necrosis factor-a pathway survival genes and of the receptor TNFR2 in gastric cancer

BACKGROUND Gastric carcinogenesis can be induced by chronic inflammation triggered by Helicobacter pylori(H. pylori) infection. Tumor necrosis factor(TNF)-α and its receptors(TNFR1 and TNFR2) regulate important cellular processes, such as apoptosis and cell survival, and the disruption of which can lead to cancer. This signaling pathway is also modulated by microRNAs(miRNAs), altering gene expression.AIM To evaluate the mRNA and miRNAs expression involved in the TNF-α signaling pathway in gastric cancer(GC) tissues and its relationship.METHODS Quantitative polymerase chain reaction(qPCR) by TaqMan? assay was used to quantify the RNA transcript levels of TNF-α signaling pathway(TNF, TNFR1,TNFR2, TRADD, TRAF2, CFLIP, NFKB1, NFKB2, CASP8, CASP3) and miRNAs that targets genes from this pathway(miR-19 a, miR-34 a, miR-103 a, miR-130 a,miR-181 c) in 30 GC fresh tissue samples. Molecular diagnosis of H. pylori was performed by nested PCR for gene HSP60. A miRNA:mRNA interaction network was construct using Cytoscape v3.1.1 from the in silico analysis performed using public databases.RESULTS Up-regulation of cellular survival genes as TNF, TNFR2, TRADD, TRAF2, CFLIP,and NFKB2, besides CASP8 and miR-34 a was observed in GC tissues, whereas mediators of apoptosis such as TNFR1 and CASP3 were down-regulated. When the samples were stratified by histological type, the expression of miR-103 a and miR-130 a was significantly increased in the diffuse-type of GC compared to the intestinal-type. However, no influence of H. pylori infection was observed on the expression levels of mRNA and miRNAs analyzed. Moreover, the miRNA:mRNA interaction network showed several interrelations between the miRNAs and their target genes, highlighting miR-19 a and miR-103 a, which has as predicted or validated target a large number of genes in the TNF-α pathway,including TNF, TNFR1, TNFR2, CFLIP, TRADD, CASP3 and CASP8.CONCLUSION Our findings show that cell survival genes mediated by TNF/TNFR2 binding is up-regulated in GC favoring its pro-tumoral effect, while pro-apoptotic genes as CASP3 and TNFR1 are down-regulated, indicating disbalance between apoptosis and cell proliferation processes in this neoplasm. This process can also be influenced by an intricate regulatory network of miRNA:mRNA.

Nurses Opinions Regarding Delirium Care in the Older General Hospital Population and in Older Cardiac Surgery Patients Specifically: A Multicentre Survey among Dutch Nurses

Background: Delirium is a high prevalent postoperative complication in older cardiac surgery patients and can have drastic consequence for the patient. Preventive interventions, diagnosis and treatment of delirium require specialized knowledge and skills. Objective: To gain insight in the current opinion and beliefs of nurses in hospitals concerning prevention, diagnosis and treatment of delirium in older hospital patients in general and specifically in older cardiac surgery patients. Methods: In a cross-sectional study from February to July 2010, we distributed a survey on beliefs on delirium care among 368 nurses in three hospitals in the Netherlands, in one hospital in all wards with older patients and in two hospitals in the cardiac surgery wards only. Results: Although in literature incidence rates up to 54.9% in cardiac surgery patients in hospitals are reported, with a response rate of 68% (250), half of the nurses believe that the incidence of delirium is not even 10%. Two thirds think that delirium in patients is preventable. Although, the Delirium Observation Scale is most often used for screening delirium, nearly all nurses do not routinely screen patients for delirium. Opinions on delirium of nurses working in cardiac surgery wards did not differ from nurses caring for older patients in other hospital wards. Conclusions: Nurses do have knowledge on delirium care, but there is a gap between the reported incidence in literature and the estimation of the occurrence of delirium by nurses. A two-way causal relationship emerges: because nurses underestimate the occurrence, they do not screen patients on a routine basis. And because they do not screen patients on a routine basis they underestimate the incidence.

Chronic proctalgia and chronic pelvic pain syndromes:New etiologic insights and treatment options

This systematic review addresses the pathophysiology, diagnostic evaluation, and treatment of several chronic pain syndromes affecting the pelvic organs:chronic proctalgia, coccygodynia, pudendal neuralgia, and chronic pelvic pain. Chronic or recurrent pain in the anal canal, rectum, or other pelvic organs occurs in 7% to 24% of the population and is associated with impaired quality of life and high health care costs. However, these pain syndromes are poorly understood, with little research evidence available to guide their diagnosis and treatment. This situation appears to be changing:A recently published large randomized,controlled trial by our group comparing biofeedback, electrogalvanic stimulation, and massage for the treatment of chronic proctalgia has shown success rates of 85% for biofeedback when patients are selected based on physical examination evidence of tenderness in response to traction on the levator ani muscle-a physical sign suggestive of striated muscle tension. Excessive tension (spasm) in the striated muscles of the pelvic floor appears to be common to most of the pelvic pain syndromes. This suggests the possibility that similar approaches to diagnostic assessment and treatment may improve outcomes in other pelvic pain disorders.

Relationship between Fusobacterium nucleatum,inflammatory mediators and microRNAs in colorectal carcinogenesis

AIM To examine the effect of Fusobacterium nucleatum(F. nucleatum) on the microenvironment of colonic neoplasms and the expression of inflammatory mediators and microRNAs(miRNAs).METHODS Levels of F. nucleatum DNA, cytokine gene mRNA(TLR2, TLR4, NFKB1, TNF, IL1 B, IL6 and IL8), and potentially interacting miRNAs(miR-21-3p, miR-22-3p, mi R-28-5p, miR-34a-5p, miR-135b-5p) were measured by quantitative polymerase chain reaction(qPCR) TaqMan? assays in DNA and/or RNA extracted from the disease and adjacent normal fresh tissues of 27 colorectal adenoma(CRA) and 43 colorectal cancer(CRC) patients. KRAS mutations were detected by direct sequencing and microsatellite instability(MSI) status by multiplex PCR. Cytoscape v3.1.1 was used to construct the postulated miRNA:mRNA interaction network.RESULTS Overabundance of F. nucleatum in neoplastic tissue compared to matched normal tissue was detected in CRA(51.8%) and more markedly in CRC(72.1%). We observed significantly greater expression of TLR4, IL1 B, IL8, and miR-135 b in CRA lesions and TLR2, IL1 B, IL6, IL8, mi R-34 a and miR-135 b in CRC tumours compared to their respective normal tissues. Only two transcripts for miR-22 and miR-28 were exclusively downregulated in CRC tumour samples. The mRNA expression of IL1 B, IL6, IL8 and miR-22 was positively correlated with F. nucleatum quantification in CRC tumours. The mRNA expression of miR-135 b and TNF was inversely correlated. The miRNA:mRNA interaction network suggested that the upregulation of miR-34 a in CRC proceeds via a TLR2/TLR4-dependent response to F. nucleatum. Finally, KRAS mutations were more frequently observed in CRC samples infected with F. nucleatum and were associated with greater expression of miR-21 in CRA, while IL8 was upregulated in MSI-high CRC.CONCLUSION Our findings indicate that F. nucleatum is a risk factor for CRC by increasing the expression of inflammatory mediators through a possible mi RNA-mediated activation of TLR2/TLR4.

Challenges in the diagnosis of intestinal neuronal dysplasia type B:A look beyond the number of ganglion cells

Intestinal neuronal dysplasia type B(IND-B)is a controversial condition among gastrointestinal neuromuscular disorders.Constipation is its most common clinical manifestation in patients.Despite intense scientific research,there are still knowledge gaps regarding the diagnostic criteria for IND-B in the histopathological analysis of rectal biopsies.The guidelines published in the past three decades have directed diagnostic criteria for quantifying the number of ganglion cells in the nervous plexus of the enteric nervous system.However,it is very complex to distinguish numerically what is pathological from what is normal,mainly because of the difficulty in determining a reliable control group composed of healthy children without intestinal symptoms.Thus,a series of immunohistochemical markers have been proposed to assist in the histopathological analysis of the enteric nervous system.Several of these markers facilitate the identification of other structures of the enteric nervous system,in addition to ganglion cells.These structures may be related to the etiopathogenesis of IND-B and represent new possibilities for the histopathological diagnosis of this disease,providing a view beyond the number of ganglion cells.This review critically discusses the aspects related to the disease definitions and diagnostic criteria of this organic cause of constipation.

Intestinal neuronal dysplasia type B:A still little known diagnosis for organic causes of intestinal chronic constipation

Intestinal neuronal dysplasia type B(IND-B) is a controversial entity among the gastrointestinal neuromuscular disorders. It may occur alone or associated with other neuropathies, such as Hirschsprung's disease(HD). Chronic constipation is the most common clinical manifestation of patients. IND-B primarily affects young children and mimics HD, but has its own histopathologic features characterized mainly by hyperplasia of the submucosal nerve plexus. Thus, IND-B should be included in the differential diagnoses of organic causes of constipation. In recent years, an increasing number of cases of IND-B in adults have also been described, some presenting severe constipation since childhood and others with the onset of symptoms at adulthood. Despite the intense scientific research in the last decades, there are still knowledge gaps regarding definition, pathogenesis, diagnostic criteria and therapeutic possibilities for IND-B. However, in medical practice, we continue to encounter patients with severe constipation or intestinal obstruction who undergo to diagnostic investigation for HD and their rectal biopsies present hyperganglionosis in the submucosal nerve plexus and other features, consistent with the diagnosis of IND-B. This review critically discusses aspects related to the disease definitions, pathophysiology and genetics, epidemiology distribution, clinical presentation, diagnostic criteria and therapeutic possibilities of this still little-known organic cause of intestinal chronic constipation.

Sorafenib after Arterial Chemoembolization in Child-Pugh A and B Cirrhotic Patients with Intermediate Hepatocellular Carcinoma: A Retrospective Analysis

Introduction: Hepatocellular carcinoma (HCC) is a leading cause of mortality among cirrhotic patients, and current guidelines recommend single-treatment modalities according to patient and liver disease classifications. New studies have shown promising results from combining locoregional and systemic treatments, but most of them were limited to Child-Pugh A patients due to toxicity concerns. Aim: The objective of this study was to analyze survival rates of Child-Pugh A and B patients with intermediate HCC tumors treated with transarterial chemoembolization (TACE) followed by full-dose sorafenib usage. Material and methods: a retrospective analysis of 37 cirrhotic patients (Child-Pugh A and B rates = 23/14) treated with TACE and TACE followed by sorafenib usage (17 and 20 patients, respectively). Results: The mean survival was 379 days in the combined treatment group and 151 days in the single-treatment group (p = 0.007). There were no differences in survival according to the Child-Pugh classification. Conclusions: sorafenib after TACE can be an option for selected cirrhotic patients with intermediate HCC tumors if this combined approach is cautiously performed on an individualized schedule. Our results suggest that the Child-Pugh classification should not be a limitation to this combined treatment.

Correlation between Cognitive Aspects and Dysphagia in Patients with Amyotrophic Lateral Sclerosis: Preliminary Report

Introduction: Cognitive impairment has been identified in 30% - 50% of the population with Amyotrophic Lateral Sclerosis (ALS). Among these patients, dysphagia is not only a very common symptom but also one of the main bulbar symptoms. Objective: To correlate cognitive function and dysphagia in patients with ALS. Methods: a cross-sectional study. Criteria for inclusion were an ALS diagnosis and the signing of the consent form. Criteria for exclusion were patients who had undergone speech therapy, patients within sufficient oral language skills to participate in cognitive tests, patients receiving enteral feeding and patients who withdrew from the study before completing all the stages. Evaluations of cognition and dysphagia were performed. Results: The initial sample consisted of 86 participants, 69 of which fell under exclusion criteria. Seventeen patients were evaluated, with a mean age of 49.8 (±11.3) and a mean education period of 7.1 (±2.8) years. Disease evolution was analyzed in months, with a median of 24 (P25 = 10;P75 = 72) months. In this sample, 70.6% of patients were male (p = 0.019). Among the tests performed, those of executive functions were correlated with dysphagia: FAB (p = 0.019) and Trail Making Test A (p = 0.006). Conclusion: This pilot study suggests a correlation between executive functions and dysphagia.

Upregulation of the APE1 and H2AX genes and miRNAs involved in DNA damage response and repair in gastric cancer

Gastric cancer remains one of the leading causes of cancer-related death worldwide,and most of the cases are associated with Helicobacter pylori infection.This bacterium promotes the production of reactive oxygen species(ROS),which cause DNA damage in gastric epithelial cells.In this study,we evaluated the expression of important genes involved in the recognition of DNA damage(ATM,ATR,and H2AX)and ROS-induced damage repair(APE1)and the expression of some miRNAs(miR-15a,miR-21,miR-24,miR-421 and miR-605)that target genes involved in the DNA damage response(DDR)in 31 fresh tissues of gastric cancer.Cytoscape v3.1.1 was used to construct the postulated miRNA:mRNA interaction network.Analysis performed by real-time quantitative PCR exhibited significantly increased levels of the APE1(RQ=2.55,p<0.0001)and H2AX(RQ=2.88,p=0.0002)genes beyond the miR-421 and miR-605 in the gastric cancer samples.In addition,significantly elevated levels of miR-21,miR-24 and miR-421 were observed in diffuse-type gastric cancer.Correlation analysis reinforced some of the gene:gene(ATM/ATR/H2AX)and miRNA:mRNA relationships obtained also with the interaction network.Thus,our findings show that tumor cells from gastric cancer presents deregulation of genes and miRNAs that participate in the recognition and repair of DNA damage,which could confer an advantage to cell survival and proliferation in the tumor microenvironment.

Biliary tract reconstruction using jejunal tube:an experimental study in dogs

BACKGROUND:To physiologically reconstruct the biliary tract,Crema et al suggested the application of the Monti principle to the biliary tract,already used in humans for the urinary tract.With this technique,a jejunal segment is transversely retubularized.This study aimed to evaluate the efficacy of jejunal tube interposition between the common bile duct and duodenum in dogs.METHODS:Thirteen dogs underwent a laparoscopic common bile duct ligature,followed by a biliodigestive connection by jejunal tube interposition after one week.The levels of glutamic-pyruvic and glutamic-oxalacetic transaminases,total bilirubins,alkaline phosphatase and gamma-glutamyltransferase were assessed before surgery and thereafter weekly until euthanasia,which was performed 6 weeks after biliodigestive connection.RESULTS:Data on 9 dogs were analyzed statistically.The dogs presented with obstructive jaundice after common bile duct ligature,as confirmed by biochemical examination.They showed a statistically significant reduction in cholestasis after biliodigestive connection by jejunal tube interposition and were healthy until the end of the experiment.CONCLUSION:A statistically significant reduction was seen in total bilirubin and canalicular enzymes(alkaline phosphatase and gamma-glutamyltransferase)in the 9 dogs 6 weeks after biliodigestive connetion by jejunal tube interposition.

Neuromodulation for fecal incontinence: An effective surgical intervention

Fecal incontinence is a disabling symptom with medical and social implications,including fear,embarrassment,isolation and even depression.Most patients live in seclusion and have to plan their life around the symptom,with secondary impairment of their quality of life.Conservative management and biofeedback therapy are reported to benefit a good percentage of those affected.However,surgery must be considered in the nonresponder population.Recently,sacral nerve electrostimulation,lately named neuromodulation,has been reported to benefit patients with fecal incontinence in randomized controlled trials more than placebo stimulation and conservative management,by some unknown mechanism.Neuromodulation is a minimally invasive procedure with a low rate of adverse events and apparently favorable cost-efficacy profile.This review is intended to expand knowledge about this effective intervention among the non-surgically skilled community who deals with this disabled group of patients.